Cost-Effectiveness Analysis of First-Line FOLFIRI Combined With Cetuximab or Bevacizumab in Patients With RAS Wild-Type Left-Sided Metastatic Colorectal Cancer.

BACKGROUND: The FIRE-3 phase III clinical trial demonstrated the marked advantage of prolonging the median overall survival of patients with final RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC) by 38.3 months after treatment with irinotecan, fluorouracil, and leucovorin (FOLFIRI) plus cetuximab and by 28.0 months after treatment with FOLFIRI plus bevacizumab. However, the substantial cost increase and economic impact of using cetuximab imposes a considerable burden on patients and society. METHODS: A Markov model based on the data collected in the FIRE-3 trial was developed to investigate the cost-effectiveness of treating patients with FOLFIRI plus either cetuximab or bevacizumab from the perspective of the Chinese health-care system. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated over a lifetime horizon. One-way and probabilistic sensitivity analyses were performed by varying potentially modifiable parameters. RESULTS: In our analysis, the total treatment costs in the bevacizumab and cetuximab groups were $92 549.31 and $94 987.31, respectively, and the QALYs gained were 1.58 and 2.05. In the base-case analysis, compared with bevacizumab, left-sided RAS WT patients receiving cetuximab gained 0.47 more QALYs at an ICER of $5187.23/QALY ($3166.23/LY). The 1-way sensitivity analysis showed that the most influential parameter was the cost of cetuximab. Probabilistic sensitivity analysis indicated that the cost-effective probability of cetuximab group was 92.8% under the willingness-to-pay threshold of $24 081. CONCLUSIONS: Treatment with FOLFIRI plus cetuximab in Chinese patients with left-sided RAS WT mCRC may improve health outcomes and use financial resources more efficiently than FOLFIRI plus bevacizumab.

In Vitro Assessment of Antitumor Potential and Combination Effect of Classical and Molecular-targeted Anticancer Drugs.

BACKGROUND/AIM: The aim of the study was to evaluate the antitumor potential and combination effects of chemotherapeutic drugs. MATERIALS AND METHODS: The cytotoxicity of 20 drip-type classical and molecular-targeted anticancer drugs was examined against 4 human oral squamous cell carcinoma cell lines and 5 human oral normal mesenchymal and epithelial cells. Cell cycle progression was monitored by a cell sorter. Combination effect was evaluated by combination index. RESULTS: Most of the classical anticancer drugs showed much higher antitumor activity than molecular-targeted drugs, except bortezomib. Among 12 classical anticancer drugs, taxanes and gemsitabine showed the highest tumor-specificity (TS) and potency-selectivity expression (PSE) values, whereas platinum analogs showed the least TS value. Combination of two classical or a classical and a molecular-targeted drug showed mostly additive or antagonistic effect. 5-FU and cisplatin did not produce a subG1 population, but induced G2/M or G1/S arrest, regardless of the addition of cetuximab. Cetuximab, nibolumab and bortezomib showed potent keratinocyte toxicity. CONCLUSION: The present TS monitoring system may provide useful information for building up the treatment regimens of anticancer drugs.

Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.

Several studies have reported that epidermal growth factor receptor (EGFR)-related molecules may serve as predictors of cetuximab treatment for metastatic colorectal cancer (mCRC), such as EGFR gene copy number (GCN), expression of 2 ligands of EGFR, amphiregulin (AREG) and epiregulin (EREG), and EGFR CA simple sequence repeat 1 (CA-SSR1) polymorphism; however, these biomarkers still remain not useful in clinical practice since they have been evaluated using cohorts with patients treated in various settings of chemotherapy. We therefore analyzed associations of mRNA expression of AREG and EREG, EGFR GCN, and CA-SSR1 polymorphism [short (S;≤ 19) / long (L; ≥ 20)] with clinical outcomes in 77 Japanese patients with KRAS exon 2 wild-type mCRC enrolled in phase II trials of FOLFOX (n = 28/57, UMIN000004197) or SOX (n = 49/67, UMIN000007022) plus cetuximab as first-line therapy. High AREG expression correlated with significantly better progression-free survival (median 11.6 vs. 66 months, HR 0.52, P = 0.037); moreover, it remained statistically significant in multivariate analysis (HR: 0.48, P = 0.027). S/S genotype of CA-SSR1 predicted severe skin toxicity (P = 0.040). Patients with both AREG-low and EGFR low-GCN had significantly shorter overall survival than the others (median 22.2 vs. 42.8 months, HR 2.34, P = 0.042). The multivariate analysis showed that molecular status with both AREG-low and EGFR low-GCN was a predictor of worse survival (P = 0.006). In conclusion, AREG mRNA expression and EGFR CA-SSR1 polymorphism predict survival and skin toxicity, respectively, of initial chemotherapy with cetuximab. Our results also suggest potential prognostic value of the combined assessment of AREG and EGFR GCN for first-line cetuximab treatment.

Assessment of the change in cetuximab-induced antibody-dependent cellular cytotoxicity activity of natural killer cells by steroid.

BACKGROUND: Epidermal growth factor receptor (EGFR)-targeted therapy has been widely accepted as a promising treatment for solid tumors. Steroid treatment is used to prevent adverse effect of anti-EGFR antibody; however, influence of steroids in the antitumor activity of targeted antibody remains poorly understood. Herein, we demonstrated the impact of steroids in induced antibody-dependent cellular cytotoxicity (ADCC) activity of natural killer (NK) cells by cetuximab. METHODS: Various numbers of NK cells from healthy donors were co-cultured with tumor and/or cetuximab with or without dexamethasone. After incubation, NK cells, ADCC activity, survival, and activation markers expression were determined. RESULTS: Clinical concentration of dexamethasone treatment clearly inhibited cetuximab-induced ADCC activity of NK cells against head and neck squamous cell carcinoma (HNSCC) and colon cancer. Dexamethasone decreased the activation marker CD69 expression on NK cells. CONCLUSION: This is the first report that shows the negative affect of steroids in cancer treatment using therapeutic antibody. Attention needs to be paid for using steroids in tumor treatment.

Personalized medicine and economic evaluation in oncology: all theory and no practice?

The clinical definition of personalized medicine (PM) is closely related to that of pharmacogenomics. Ideally, PM could lead the pharmaceutical industry to differentiate products by subgroups of patients with the same pathology and find new gene targets for drug discovery. Here, we focus on the potential impact of PM on the design of clinical trials and economic evaluations limited to oncology (its first and main field of application). Then, we assess the European economic evaluations focused on trastuzumab and cetuximab, the two drugs usually mentioned as emblematic examples of targeted therapies. Clinical results of PM in oncology have not been as encouraging as hoped so far. Of course, economic evaluations on targeted therapies cannot help overcome the lack of clinical evidence for most of them. The two paradigmatic examples of cetuximab and trastuzumab indicate that the methodological implications on economic evaluations debated in the literature are more theoretical than practical.

Xenograft assessment of predictive biomarkers for standard head and neck cancer therapies.

Head and neck squamous cell carcinoma (HNSCC) remains a challenging cancer to treat with overall 5-year survival on the order of 50-60%. Therefore, predictive biomarkers for this disease would be valuable to provide more effective and individualized therapeutic approaches for these patients. While prognostic biomarkers such as p16 expression correlate with outcome; to date, no predictive biomarkers have been clinically validated for HNSCC. We generated xenografts in immunocompromised mice from six established HNSCC cell lines and evaluated response to cisplatin, cetuximab, and radiation. Tissue microarrays were constructed from pre- and posttreatment tumor samples derived from each xenograft experiment. Quantitative immunohistochemistry was performed using a semiautomated imaging and analysis platform to determine the relative expression of five potential predictive biomarkers: epidermal growth factor receptor (EGFR), phospho-EGFR, phospho-Akt, phospho-ERK, and excision repair cross-complementation group 1 (ERCC1). Biomarker levels were compared between xenografts that were sensitive versus resistant to a specific therapy utilizing a two-sample t-test with equal standard deviations. Indeed the xenografts displayed heterogeneous responses to each treatment, and we linked a number of baseline biomarker levels to response. This included low ERCC1 being associated with cisplatin sensitivity, low phospho-Akt correlated with cetuximab sensitivity, and high total EGFR was related to radiation resistance. Overall, we developed a systematic approach to identifying predictive biomarkers and demonstrated several connections between biomarker levels and treatment response. Despite these promising initial results, this work requires additional preclinical validation, likely involving the use of patient-derived xenografts, prior to moving into the clinical realm for confirmation among patients with HNSCC.

Assessment of caroverine as a potential chemotherapeutical agent in HNSCC cell lines.

Since the prognosis of head and neck squamous cell carcinoma (HNSCC) still remains poor, identifying novel chemotherapeutic agents is of outmost importance. The anticancer potential of quinoxalines has been described in various tumor entities. Caroverine, also a quinoxaline derivative, has been shown to suppress tumor promotion factors. The aim of this study was to evaluate the effect of caroverine on HNSCC cell lines. The HNSCC cell lines SCC9, SCC25, CAL27, and FaDu were incubated with caroverine alone or in combination with cisplatin, 5-fluorouracil (5-FU) or cetuximab. Cell viability was measured using the CCK-8 assay. The murine 3T3 fibroblast cell line was used to address tissue specificity. Apoptosis was visualized by immunohistochemistry. Caroverine showed a dose-dependent growth inhibition in all cell lines, IC50 values ranged from 75.69 to 179.80 µM. This effect was increased when caroverine was combined with cetuximab or 5-FU. Immunohistochemistry displayed more apoptosis after caroverine treatment compared to controls. Furthermore, caroverine alone had no growth inhibitory effect on 3T3 cells. For the first time, this study provides evidence that caroverine may serve as a supportive drug in the treatment of HNSCC patients.